The effect of iononotropic glutamate receptor agonists was studied in primary cultures of mesencephalic neurons. Exposure of cells to 10 mM (alpha-amino-3-hydroxy-5-methyl isoxazole-4-propionic acid HBr (AMPA), glutamate, kainate or quisqualate for 1-5 min increased [Ca2+]i by 2 to 3 fold in dopaminergic, and nondopaminergic neurons. The increase of [Ca2+]i was obliterated by superfusion with agonist-free incubation medium. Exposure to 50 mM of the same acids increased [Ca2+]i by 3-5 fold over control and was reversible by wash-out only in nondopaminergic neurons, but irreversible in dopaminergic neurons. Cell death of dopaminergic neurons was manifested by propidium iodide uptake 6-7 hrs after exposure. Preincubation of cultured neurons with nifedipine, a voltage-dependent Ca2+ channel blocker, NBQX, an AMPA receptor antagonist, or dantrolene, a blocker of Ca2+-dependent Ca2+ release from intracellular stores prevented the destabilization of Ca2+ homeostasis in dopaminergic neurons. The increased vulnerability of dopaminergic neurons to excitatory amino acids may be of pathological relevance during ontogenesis.